The native gonadoliberine peptide hormone of hypothalamic origin liberates the luteinising hormone (hereinafter LH) controlling the sexual processes and follicus stimulating hormone (hereinafter FSH). Through these hormones the rutting, ovulation, spermatogenesis, etc. which processes basically determine the natural proliferation of vertebrates may be stimulated or inhibited. On the bases of recent research the use of GnRH analogues in the therapy of prostata and malignant tumors seems to be promising.
Hungarian Patent Specification No. 165,546 describes the synthetic preparation of native GnRH. According to this known process the GnRH is prepared by condensing 6+4 fragments. In U.S. Pat. No. 3,888,836 the compound is built up step by step.
Knowing the therapeutical utility of GnRH, a high number of analogues were prepared of which the so-called superactive GnRH analogues are of especial importance. It is known (J. Sandow et al, Control of Ovulation, Butterworths, London, 1978: v. 49-70.) that if the Gly group being in position 6 of the native GnRH is replaced by any .alpha.-amino acid of D-configuration, the LH liberating effect of the GnRH analogue as well as the duration of the effect are highly increased.
In Belgian Patent Specification No. 897,455 such GnRH analogues are described, wherein the Gly group being in position 6 is replaced by a D-1-amino-3,3-dimethyl-1-butanoic acid.
U.S. Pat. No. 4,410,514 relates to superactive GnRH analgues wherein the 6-Gly is replaced by D-Trp, -Ala, Phe, -Lys, -Pro, -Met, -Leu, Glu, -Asn, -Arg, -Tyr, -Cys, -His, -Chg, -Nva, -Orn, Thr, -Abu, -Phg, -Ile,-Gln,-Asp,-Nle or -Val and the C-terminal Gly group is optionally missing and/or substituted. The target compounds are suggested to be used for the therapy of fishes.
U.S. Pat. No. 4,382,922 describes the 6-D-Phe GnRH analogues, while German Published Patent Application No. 24 38 350 relates to GnRH analogues having substituted D-Ser, Cys, Asp, Glu, Orn, and Lys groups in position 6. In Swiss Patent Specification No. 603,559 the amino acid groups being in positions 5, 6 and 7 are replaced by other amino acid groups mainly of D configuration. The prior art refers to numerous other publications relating to superactive GnRH analogues. The common feature of these analogues is that the amino acid group being in position 6 is derived from a non-native amino acid.
Those analogues wherein a .beta.-amino acid is in position 6 have also a high GnRH activity (Hungarian patent specification No. 187,503).
The GnRH analogue wherein an L-gamma-lactame ring is in positions 6 and 7 also exhibits significant biological activity. [Science, 210, 656 (1980)]
It can be stated that all of the known analogues of GnRH comprise at least one structural element which cannot be found in nature. However, it is very favorable from the therapeutical point of view of peptide hormones of endogenic activity if the compound comprises exclusively native amino acids and it can be substantiated that the metabolic products of the active ingredient will not cause undesired side-effects.
The aim of our work was to develop GnRH analogues having more long lasting and higher LH liberating activity than the natural GnRH which are built up exclusively from L-.alpha.-amino acids.
Surprisingly we found that the compounds of formula I comprising no D-amino acid have much higher efficacity for liberating the LH hormone than the natural GnRH.